JP6407444B2 - トリフルオロアセトヒドラジド類化合物及びその調製方法並びに製薬における応用 - Google Patents
トリフルオロアセトヒドラジド類化合物及びその調製方法並びに製薬における応用 Download PDFInfo
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- JP6407444B2 JP6407444B2 JP2017535706A JP2017535706A JP6407444B2 JP 6407444 B2 JP6407444 B2 JP 6407444B2 JP 2017535706 A JP2017535706 A JP 2017535706A JP 2017535706 A JP2017535706 A JP 2017535706A JP 6407444 B2 JP6407444 B2 JP 6407444B2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C241/00—Preparation of compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Description
また、本発明は前記トリフルオロアセトヒドラジド類化合物が製薬における用途及び疾患の予防と治療における応用を提供する。
R1,R2,R3は同一若しくは異なって、それぞれ独立にH、OH、NH2、COOH、アルキル基、アリール基、ヘテロアリール基、脂質基、アミン基またはカルバメートであり、但し同時にHであることができない。
2,4- ジメチルフェニルヒドラジン塩酸塩(1.72g, 10 mmol)を10 mLのメタノールに溶解し、N2の保護の下で氷浴で3,5,6-トリメチルピラジン-2-ホルムアルデヒド(1.50 g, 12 mmol)を加え、10 min撹拌した後に大量の赤れんが色の沈殿物が析出するまで反応を続ける。吸引漏斗で吸引ろ過して得られた赤れんが色の固体は真空の乾燥箱に移して乾燥した後、直接に次の反応に入る。赤れんが色中間体(3.04 g, 10 mmol)を25mLのメタノールに溶解しN2の保護の下で氷浴で1.68 mlの無水トリエチルアミンと1.7 mlのトリフルオロ酢酸無水物を加え30 min反応させる。TLCで反応を監視し、反応終了後、酢酸エチルで抽出し、無水Na2SO4で乾燥し、減圧して溶剤を蒸発乾固する。シリカゲルカラムで分離させ(酢酸エチル:石油エーテル=1 : 3)、淡黄色固体(3.25 g,89.3%)T-006を得る。ESI-MS: [M+H]+ m/z 365.1. 1H-NMR (CDCl3, 300 MHz) δ: 2.1(s, 3H), 2.42 (s, 3H), 2.46 (s, 3H), 2.54 (s, 3H), 2.85 (s, 3H),7.08 (d, j = 7.05 Hz, 1H),7.24 (d, J = 7.21 Hz, 1H), 7.25(s, 1H), 7.55 (s,1H); Anal. (C18H19F3N4O) C, H, C; found C 59.44%, H 5.319%, N 15.23%; requires: C 59.33%, H 5.26%, N 15.38%。
PC12細胞を96有孔板に接種して、37℃、5% CO2の培養器に24時間培養した後、100 μl IAA(50 μM)を加えて2時間誘導する。2時間後、培地を吸い出し、各化合物(T-006, TMP, Edaravone)を加えて24時間培養する。その後、各孔にMTTを入れ、4時間後、マイクロプレートリーダーで570nmの吸光度を測定する。その結果として、図3の示すように、T-006はIAA誘導PC12細胞損傷に対して顕著な保護作用を有し、且つ母体化合物TMP及びEdaravoneより遥かに強い。IAA組と比べて****P<0.0001。
PC12細胞を96有孔板に接種して37℃、5% CO2の細胞培養器に24時間培養した後、濃度勾配の異なる各化合物(T-006, TMP, Edaravone)を加えて2時間プレインキュベーションする。2時間後、培地を吸い出し、Control組を除いて各孔に100 μl t-BHP(100μM)を入れ、培養器に24時間培養した後、各孔にMTTを入れ、4時間後、マイクロプレートリーダーで570 nmの吸光度を測定する。その結果として、図4の示すように、T-006はt-BHP誘導PC12細胞損傷に対して顕著な保護作用を有し、且つ母体化合物TMP及びEdaravoneより遥かに強い。t-BHP組と比べて****P<0.0001。
E16〜18日のSDマウス胎児皮質ニューロンを96有孔板に接種して37℃、5%CO2の培養器に8日まで培養する。同時に濃度勾配の異なる各化合物(T-006, TMP, Edaravone)を50μl加えControl組を除いて各孔に50μl IAA(40μM)を入れる。培養器に24時間培養した後、各孔にMTTを入れ、4時間後、マイクロプレートリーダーで570 nmの吸光度を測定する。その結果として、図5の示すように、T-006はIAA誘導皮質ニューロン損傷に対して顕著な保護作用を有し、且つ母体化合物TMP及びEdaravoneより遥かに強い。IAA組と比べて****P<0.0001。
E16〜18日のSDマウス胎児皮質ニューロンを96有孔板に接種して37℃、5%CO2の培養器に8日まで培養する。同時に濃度勾配の異なる各化合物(T-006, TMP, Edaravone)を50μl加えControl組を除いて各孔に50 μl t-BHP(50 μM)を入れる。培養器に24時間培養した後、各孔にMTTを入れ、4時間後、マイクロプレートリーダーで570 nmの吸光度を測定する。その結果として、図6の示すように、T-006はt-BHP誘導皮質ニューロン損傷に対して顕著な保護作用を有し、且つ母体化合物TMP及びEdaravoneより遥かに強い。t-BHP組と比べて****P<0.0001。
初代小脳顆粒細胞は生後7〜8日、15〜20gのSD乳飲みマウスから抽出され、37℃、5%CO2の培養器に8日まで培養する。濃度勾配の異なる各化合物(T-006)を90μl加えて培養器に2時間孵化し、Control組を除いて各孔に10μl glutamate(最終濃度75μM)を入れる。培養器に24時間培養した後、各孔にMTTを入れ、4時間後、マイクロプレートリーダーで570 nmの吸光度を測定する。その結果として、図7の示すように、T-006はglutamate誘導小脳顆粒細胞損傷に対して顕著な保護作用を有し、且つ良い濃度依存性を示す。glutamate組と比べて**P<0.01。
初代小脳顆粒細胞は生後7〜8日、15〜20gのSD乳飲みマウスから抽出され、37℃、5%CO2の培養器に8日まで培養する。濃度勾配の異なる各化合物(T-006)を90 μl加えて培養器に2時間孵化し、Control組を除いて各孔に10μl MPP+ (最終濃度35μM)を入れる。培養器に24時間培養した後、各孔にMTTを入れ、4時間後、マイクロプレートリーダーで570 nmの吸光度を測定する。その結果として、図8の示すように、T-006はMPP+誘導小脳顆粒細胞損傷に対して顕著な保護作用を有し、且つ良い濃度依存性を示す。MPP+組と比べて**P<0.01。
MEF2レポーター遺伝子 pGreenFire1TM-MEF2-EF1レンチウイルスべクター(lentivector)をクローンすることによってPC12をトランスフェクションする。安定トランスフェクションされたPC12細胞を普通の方法で培養し、96有孔板に接種して、粘着した後、濃度勾配の異なるT-006を加えて24時間孵化し、ルシフェラーゼレポーター遺伝子試薬キット(Luciferase reporter assay kit, Promega, USA)方法で活性を測定する。その結果として、図9の示すようにT-006がPC12細胞のMEF2転写活性を顕著に活性化できる。IAA組と比べて**P<0.01。
本実験は昆明マウスを採用する。それを正常対照組(control, Ctrl)、スコポラミンモデル組(Scopolamine, Sco)、ドネペジル治療組(Sco+3 mg/kg donepezil)、1 と10 mg T-006治療組(Sco+1 mg/kg T-006和Sco+1 mg/kg T-006)に分ける。2週間連続で胃内注入の方式で投薬し、最終回に24h投薬し、水迷路試験訓練を行い、4日続ける。訓練前の30 minに腹腔にスコポラミンモデル(1mg/kg)を注射して、モデルを作る。第5日は空間捜索実験である。データはMean± SDで表示される(各組の動物n=9)。その結果として、図10 Aと図10Bの示すように、スコポラミン誘導マウスの記憶が明かに損傷され、初めてプラットフォームに着く潜伏期は顕著に延長し、ターゲットプラットフォームを通す回数は減少し(正常対照組と比較して、##p<0.01)、1と10mgT-006治療組及び3 mg/kgドネペジル治療組はスコポラミンモデル誘導の記憶損傷を顕著に改善でき(スコポラミンモデル組と比較して、**p<0.01)、且つ10mg/kgT-006の治療効果は3mg/kgドネペジル($p < 0.05)より明らかに優れている。
PC12細胞を6有孔板に接種して37℃、5%CO2の培養器に24時間培養する。Control組培地が変えず、NGF対照組には、無血清F-12K + 50 ng/ml NGF、薬物処理組は濃度の異なるT-006を含む無血清F-12Kを使って、72時間孵化した後、倒立顕微鏡で撮影し、各孔にランダムに5つの視野を撮り、例えば、細胞シナプスの長さが細胞体の二倍を超えると、細胞分化、シナプス形成と見なす。その結果として、図11の示すように、T-006と陽性対照NGFが何れもPC12細胞の分化、シナプスの生成と伸長を顕著に促し、かつ濃度依存性を呈する。Control組と比べて**P < 0.01。
水酸基フリーラジカル(OH●):フェナントロリン-金属イオン-H2O2を採用して Fenton 反応 (H2O2 + Fe2+ → ・OH + H2O + Fe3+)を通じて、水酸基フリーラジカルを生成し、フェナントロリン-Fe2+をフェナントロリン-Fe3+に酸化させ、その水溶液が波長440nmに最大消失し、その消去率を測量して計算する。具体的なステップは下記のとおりである。48有孔板に300μLの再蒸留水(ブランク)或いは濃度の異なるT-006、TMP、Edaravone(DMSOで溶解し10 mMの貯蔵液を配合してから、再蒸留水で4μM、20μM、80μM、320μMに希釈する)を入れ、50μL of 1.0 mMのフェナントロリン (50 mM NaCl溶液に溶解して1.0mMを配合する)を加えて、そして、それぞれ125 μL 1.0 mM H2O2と125 μL 2.0 mM Fe2+を入れて均一に混合し、BioTek Synergy HTマイクロプレートリーダーで100秒内の440 nm波長の吸光度の減少百分率を測定する。水酸基フリーラジカル消去率計算公式は消去率(%)= [1−(A0−A100)/A0]×100 %で、A0とA100はそれぞれ0秒と100秒の時の光吸収値である。
PC12細胞を96有孔板に接種して37℃、5% CO2の培養器に24時間培養した後、濃度勾配の異なるT-006 とTMP (100μM)を加えて2時間プレインキュベートする。2時間後、培地を吸い出し、Control組を除いて各孔に100 μl t-BHP(100 μM)を入れ、培養器に置いて24時間培養した後、Hoechst作動液を入れ、蛍光顕微鏡で観察してPC12細胞アポトーシスの数を統計する。(A) T-006はt-BHP誘導のPC12細胞アポトーシスを減少する。(B)PC12細胞アポトーシスの数を統計する。(C)T-006は t-BHP誘導のPC12細胞ミトコンドリア膜電位紊乱作用を改善する。PC12細胞を96有孔板に接種して37℃、5% CO2の培養器に24時間培養した後、濃度勾配の異なるT-006 と TMP (100μM)を加えて2時間プレインキュベーションする。2時間後、Control組を除いて各孔に100 μl t-BHP(100 μM)を入れて誘導する。誘導完了後、各孔にJC-1作動液を入れ、フローサイトメーターでミトコンドリア膜電位測定分析を行う。control組と比べて、###p<0.001; t-BHPと比べて、*p<0.05, **p<0.01 and ***p<0.001。
PC12細胞を96有孔板に接種して37℃、5% CO2の培養器に24時間培養した後、濃度勾配の異なるT-006 とTMP (100μM)を加えて2時間プレインキュベートする。2時間後、培養基を吸収しControl組を除いて各孔に100μl t-BHP(100 μM)を入れ、培養器に6 時間培養した後、それぞれDCF-DAプローブ、HFPプローブ、DAF-FMプローブとDHR123プローブを入れて、細胞内のROS総量、水酸基フリーラジカル、一酸化窒素フリーラジカルと過酸化亜硝酸を測定する。(A)DCF-DAプローブで細胞内のROS総量を測定する。(B)HFPプローブで細胞内の水酸基フリーラジカルを測定する。(C)DAF-FMプローブで一酸化窒素フリーラジカルを測定する。(D)DHR123プローブで細胞内の過酸化亜硝酸を測定する。control組と比べて、###p<0.001; t-BHPと比べて、*p<0.05, **p<0.01 and ***p<0.001。
Claims (9)
- 一般式Ιの構造を有するトリフルオロアセトヒドラジド類化合物であり、
- 前記アルキル基は低級アルキル基である、請求項1に記載の化合物。
- R1,R2とR3は何れもメチル基であり、下記式IIの構造を有する、請求項1又は2に記載の化合物。
- 3,5,6-トリメチル-2-ピラジンホルムアルデヒドと2,4-ジメチルフェニルヒドラジン塩酸塩を縮合して得た中間体フェニルヒドラゾンをトリフルオロ酢酸無水物と反応して最終化合物を得ることを含む、請求項1〜3のいずれかに記載の化合物の調製方法。
- 医薬品が予防または治療に利用される疾患はグルタミン酸興奮毒性、MEF2の機能障害、酸化ストレス損傷もしくはフリーラジカルに関する疾患、または神経変性疾患である、請求項1〜3のいずれかに記載の化合物の医薬品を製造するための使用。
- 前記グルタミン酸興奮毒性に関する疾患はアルツハイマー病、パーキンソン病、ハンチントン舞踏病、筋萎縮性側索硬化症、重症筋無力症、緑内障、老人性痴呆症、甲状腺機能亢進症、高血圧、気管支喘息、IV型高リポタンパク血症、または腎不全である、請求項5に記載の使用。
- 前記MEF2機能障害に関する疾患はパーキンソン病、アルツハイマー病、痴呆症、ハンチントン舞踏病、筋萎縮性側索硬化症、または重症筋無力症である、請求項5に記載の使用。
- 前記酸化ストレス損傷もしくはフリーラジカルに関する疾患は脳卒中、脳外傷、癲癇、パーキンソン病、ハンチントン舞踏病、筋萎縮性側索硬化症、アルツハイマー病、 低酸素虚血性脳障害、脳溢血、痴呆症、虚血性心疾患、血管塞栓、粥状動脈硬化症、高コレステロール血症、肺気腫、白内障、糖尿病、急性膵炎、アルコール性肝疾患、腎臓損傷、または癌である、請求項5に記載の使用。
- 前記神経変性疾患は脳虚血、パーキンソン病、アルツハイマー病、筋萎縮性側索硬化症、毛細血管拡張性運動失調症、牛海綿状脳症、クロイツフェルト・ヤコブ病、ハンチントン舞踏病、小脳萎縮症、多発性硬化症、原発性側索硬化症、または脊髄性筋萎縮症である、請求項5に記載の使用。
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